Involvement of c-Src kinase in the regulation of TGF-/β1-induced apoptosis

Seok Soon Park, Young Woo Eom, Eun Hee Kim, Ji Hyun Lee, Do Sik Min, Sungsub Kim, Seong Jin Kim, Kyeong Sook Choi

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Abstract

Transforming growth factor-β1 (TGF-β1) is a potent inducer of apoptosis in normal hepatocytes, and acquiring resistance to TGF-β1 may be a critical step in the development of hepatocellular carcinoma (HCC). In this study, we investigated the possible involvement of c-Src in the regulation of TGF-β1-induced apoptosis. TGF-β1 induced transient activation of c-Src and its subsequent caspase-mediated degradation concomitant with cell death in FaO hepatoma cells, which are sensitive to TGF-β1. In response to TGF-β1, activated c-Src was translocated into the cytoplasmic membrane, then relocated to the nuclei of apoptotic cells during its cleavage. In TGF-β1-induced apoptotic cells, c-Src maintained its tight association with p85 FAK fragment cleaved by caspases, possibly contributing to focal adhesion disassembly. TGF-β1-induced apoptosis was enhanced by either inhibition of c-Src activity using PP1 or PP2, or by overexpression of dominant-negative c-Src. In contrast, overexpression of constitutively active c-Src inhibited apoptosis suppressing TGF-β1-induced activation of p38, JNK and caspases. In many HCC cell lines resistant to TGF-β1, enhanced c-Src activity was detected. We hypothesize that activated c-Src in HCC may contribute to resistance against the apoptotic and/ or antiproliferative properties of TGF-β1.

Original languageEnglish
Pages (from-to)6272-6281
Number of pages10
JournalOncogene
Volume23
Issue number37
DOIs
Publication statusPublished - 2004 Aug 19

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Park, S. S., Eom, Y. W., Kim, E. H., Lee, J. H., Min, D. S., Kim, S., Kim, S. J., & Choi, K. S. (2004). Involvement of c-Src kinase in the regulation of TGF-/β1-induced apoptosis. Oncogene, 23(37), 6272-6281. https://doi.org/10.1038/sj.onc.1207856